An optimized ionizable cationic lipid for brain tumor-targeted siRNA delivery and glioblastoma immunotherapy
Biomaterials. 2022 Jun 22;287:121645. doi: 10.1016/j.biomaterials.2022.121645. Online ahead of print.ABSTRACTGlioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a high mortality rate. Immunotherapy has achieved promising clinical results in multiple cancers, but shows unsatisfactory outcome in GBM patients, and poor drug delivery across the blood-brain barrier (BBB) is believed to be one of the main limitations that hinder the therapeutic efficacy of drugs. Herein, a new cationic lipid nanoparticle (LNP) that can efficiently deliver siRNA across BBB and target mouse brain is prepared for modulating the tumor microenvironment for GBM immunotherapy. By designing and screening cationic LNPs with different ionizable amine headgroups, a lipid (named as BAMPA-O16B) is identified with an optimal acid dissociation constant (pKa) that significantly enhances the cellular uptake and endosomal escape of siRNA lipoplex in mouse GBM cells. Importantly, BAMPA-O16B/siRNA lipoplex is highly effective to deliver siRNA against CD47 and PD-L1 across the BBB into cranial GBM in mice, and downregulate target gene expression in the tumor, resulting in synergistically activating a T cell-dependent antitumor immunity in orthotopic GBM. Collectively, this study offers an effective strategy for brain targeted siRNA delivery and gene silencing by optimizing the physicochemical property of LNPs. The effectiveness of modulating immune environment of GBM could further b...
Source: Biomaterials - Category: Materials Science Authors: Shuhan Liu Ji Liu Haisong Li Kuirong Mao Haorui Wang Xiandi Meng Jialiang Wang Chenxi Wu Hongmei Chen Xin Wang Xiuxiu Cong Yue Hou Ye Wang Ming Wang Yong-Guang Yang Tianmeng Sun Source Type: research
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